Characterization of a novel metabolic strategy used by drug‐resistant tumor cells

Harper, Mary‐Ellen; Antoniou, A.; Villalobos-Menuey, Elizabeth; Russo, Alicia A.; Trauger, Richard; Vendemelio, Minda; George, Amanda M.; Bartholomew, Richard M.; Carlo, Dennis J.; Shaikh, A.; Kupperman, Jami; Newell, Evan W.; Bespalov, Ivan A.; Wallace, Susan S.; Liu, Ye; Rogers, Jeffrey R; Gibbs, Gregory L; Leahy, Jack L.; Camley, R. E.; Melamede, Robert J.; Newell, M. K.

doi:10.1096/fj.02-0541com

Cited by 157 publications

(141 citation statements)

References 25 publications

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“…Although very little is known about the effects of cisplatin on the mitochondria of tumor cells (36), a recent study showed that it might have direct impact on mitochondria in head and neck cancer (37). Mitochondrial defects are associated with the cisplatin resistance phenotype (38), and several hypotheses have been suggested to explain this observation. A more negative membrane potential might promote translocation of the active, cationic form of cisplatin from the cytoplasm to mitochondria, thus diminishing platination of nuclear DNA.…”

Section: Resultsmentioning

confidence: 99%

Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate

Dhar¹,

Lippard

2009

Proc. Natl. Acad. Sci. U.S.A.

344

236

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Section: Resultsmentioning

confidence: 99%

Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate

Dhar¹,

Lippard

2009

Proc. Natl. Acad. Sci. U.S.A.

344

236

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“…Recently, cross talk between cell death and the ability of cells to utilize a variety of carbon substrates has begun to be established, 27 and the switch from one substrate to another can have protective effects on a cell fate. 45,46 The generation of S49 (OS 4-25) cells has resulted in a carbon substrate reprogramming characteristic of the Warburg effect, which we show offers a selective survival advantage to these cells and has a critical role in whether a cell lives or dies. Collectively, our data suggest that repetitive stress and recovery results in genetic changes that are not restricted to commonly studied pro-or antiapoptotic genes, and these genetic changes result in a modification of carbon substrate utilization for energy production that impinges on the cell's ability to activate or signal apoptosis.…”

Section: Figure 3 Continuedmentioning

confidence: 85%

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

et al. 2015

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We developed a model system to investigate apoptotic resistance in T cells using osmotic stress (OS) to drive selection of deathresistant cells. Exposure of S49 (Neo) T cells to multiple rounds of OS followed by recovery of surviving cells resulted in the selection of a population of T cells (S49 ) that failed to die in response to a variety of intrinsic apoptotic stimuli including acute OS, but remained sensitive to extrinsic apoptotic initiators. Genome-wide microarray analysis comparing the S49 (OS 4-25) with the parent S49 (Neo) cells revealed over 8500 differentially regulated genes, with almost 90% of those identified being repressed. Surprisingly, our data revealed that apoptotic resistance is not associated with expected changes in pro-or antiapoptotic Bcl-2 family member genes. Rather, these cells lack several characteristics associated with the initial signaling or activation of the intrinsic apoptosis pathway, including failure to increase mitochondrial-derived reactive oxygen species, failure to increase intracellular calcium, failure to deplete glutathione, failure to release cytochrome c from the mitochondria, along with a lack of induced caspase activity. The S49 (OS 4-25) cells exhibit metabolic characteristics indicative of the Warburg effect, and, despite numerous changes in mitochondria gene expression, the mitochondria have a normal metabolic capacity. Interestingly, the S49 (OS 4-25) cells have developed a complete dependence on glucose for survival, and glucose withdrawal results in cell death with many of the essential characteristics of apoptosis. Furthermore, we show that other dietary sugars such as galactose support the viability of the S49 (OS 4-25) cells in the absence of glucose; however, this carbon source sensitizes these cells to die. Our findings suggest that carbon substrate reprogramming for energy production in the S49 (OS 4-25) cells results in stimulusspecific recognition defects in the activation of intrinsic apoptotic pathways.

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“…Indeed, UCP2 null mice on various genetic backgrounds exhibit oxidative stress in many tissue types and a decrease in the circulating glutathione (GSH)/glutathione disulfide ratio (2,12). Increased expression of UCP2 in cancer cells is associated with the acquisition of drug-resistant phenotypes, a phenomenon related to the ROS-quenching function of UCP2 (17,18). The absence of UCP3 in skeletal muscle increases oxidative damage and perturbs skeletal muscle metabolism (19).…”

mentioning

confidence: 99%

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

Mailloux

Seifert

Bouillaud

et al. 2011

Journal of Biological Chemistry

159

149

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The mitochondrial uncoupling proteins 2 and 3 (UCP2 and -3) are known to curtail oxidative stress and participate in a wide array of cellular functions, including insulin secretion and the regulation of satiety. However, the molecular control mechanism(s) governing these proteins remains elusive. Here we reveal that UCP2 and UCP3 contain reactive cysteine residues that can be conjugated to glutathione. We further demonstrate that this modification controls UCP2 and UCP3 function. Both reactive oxygen species and glutathionylation were found to activate and deactivate UCP3-dependent increases in nonphosphorylating respiration. We identified both Cys 25 and Cys 259 as the major glutathionylation sites on UCP3. Additional experiments in thymocytes from wild-type and UCP2 null mice demonstrated that glutathionylation similarly diminishes non-phosphorylating respiration. Our results illustrate that UCP2-and UCP3-mediated state 4 respiration is controlled by reversible glutathionylation. Altogether, these findings advance our understanding of the roles UCP2 and UCP3 play in modulating metabolic efficiency, cell signaling, and oxidative stress processes.UCP2 and -3 belong to the mitochondrial anion carrier family and are ϳ73% homologous to each other, and they are both ϳ58% homologous to the highly thermogenic uncoupling protein, UCP1. Whereas UCP3 is expressed in skeletal muscle and brown adipose tissue (BAT) 3 and to some extent in the heart, UCP2 is found in a wide variety of tissues (1). UCP2 and UCP3 have been shown to diminish oxidative stress by lowering the mitochondrial membrane potential (2, 3). Acute increases in reactive oxygen species (ROS) production increase proton conductance through both UCP2 and UCP3, providing a negative feedback loop to limit further mitochondrial ROS formation (4, 5). Furthermore, UCP2 and UCP3 have also been implicated in many physiologic functions, suggesting that the common underlying mechanism may be ROS-mediated cell signaling.Previous work has reported that UCP3 protects against insulin resistance and obesity (6 -9), whereas UCP2 has been implicated a broad range of functions, including hormone secretion from the pancreas, immune cell function, and feeding behavior (10 -13). For UCP2, most of these functions are linked to ROS level buffering (14 -16). Indeed, UCP2 null mice on various genetic backgrounds exhibit oxidative stress in many tissue types and a decrease in the circulating glutathione (GSH)/glutathione disulfide ratio (2, 12). Increased expression of UCP2 in cancer cells is associated with the acquisition of drug-resistant phenotypes, a phenomenon related to the ROS-quenching function of UCP2 (17, 18). The absence of UCP3 in skeletal muscle increases oxidative damage and perturbs skeletal muscle metabolism (19). Increased UCP3 expression in muscle augments fatty acid metabolism and also curtails ROS production during fatty acid oxidation (20,21). Remarkably, although they have been linked to a plethora of cellular processes, the molecular control of UCP2 and UCP3 ha...

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Characterization of a novel metabolic strategy used by drug‐resistant tumor cells

Cited by 157 publications

References 25 publications

Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate

Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate

T-cell development of resistance to apoptosis is driven by a metabolic shift in carbon source and altered activation of death pathways

Glutathionylation Acts as a Control Switch for Uncoupling Proteins UCP2 and UCP3

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